Diabetic retinopathy is clinically defined as a disease of the retinal microvasculature, and most research on its pathogenesis to date has focused on molecular and metabolic defects within the blood vessel cells themselves. In recent years, a few papers have suggested that cells in the outer retina might play a role the development of diabetic retinopathy, but there has been little follow-up pertaining to these ideas. The current application will investigate the hypothesis that photoreceptors play a key role in initiation of the degenerative vascular lesions in early stages of diabetic retinopathy, and that this process is initiated by oxidative stress in the photoreceptor cells. Oxidative stress is known to regulate expression of pro-inflammatory proteins, and previous studies by us have implicated an important role of inflammation in the early stages of the retinopathy. Thus, the central hypothesis of our proposal is that the photoreceptors generate superoxide and other reactive products in diabetes, and that these abnormalities initiate (via local inflammatory changes in the inner retina) the structural and functional changes of the microvasculature which are clinically recognized as early diabetic retinopathy. We further predict that oxidative and inflammatory effects on the retinal vasculature in diabetes will be exacerbated by darkness, and can be inhibited with light. The research proposed will use mouse models in which photoreceptors degenerate or are functionally impaired with respect to visual cycle activity or phototransduction, or wildtype animals. Diabetes will be induced experimentally. Specific Aims will be: (1) to differentiate the roles of photoreceptors, phototransduction and visual cycle activity in the development of the diabetes-induced vascular lesions of early diabetic retinopathy, (2) to evaluate the mechanisms by which photoreceptors contribute to the retinal oxidative stress and induction of pro-inflammatory proteins in diabetes (which have been shown to contribute to the vascular lesions of early diabetic retinopathy), and (3) to determine if inhibition of oxidative stress in photoreceptors results in inhibition of diabetes-induced defects in retinal vascular structure and function. Aim 3 will be tested using mice having (i) photoreceptor-specific knockdown of NADPH oxidase (and for comparison, (ii) systemic inhibition of NADPH oxidase), and (iii) far-red light therapy. This is a highly novel and testable hypothesis that will be conducted by an experienced research team.